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RNA-Seq of KRAS-regulated genes in a KPAR1.3-G12C murine cell line and lung tumours

ABSTRACT: RNA-Seq of KRAS-regulated genes in a KPAR1.3-G12C murine cell line and lung tumours

PROVIDER: PRJNA820755 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18505615.fastq.gz	Fastqsanger.gz
	SRR18505616.fastq.gz	Fastqsanger.gz
	SRR18505617.fastq.gz	Fastqsanger.gz
	SRR18505618.fastq.gz	Fastqsanger.gz
	SRR18505619.fastq.gz	Fastqsanger.gz

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RNA-Seq of KRAS-regulated genes in a KPAR1.3-G12C murine cell line and lung tumours

Project description:KPAR1.3-G12C murine lung cancer cell line, and derived lung tumours, were treated with a KRASG12C inhibitor for different time points

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SHP2 Inhibition Abrogates Adaptive Resistance to KRAS-G12C-Inhibition and Remodels the Tumor Microenvironment of KRAS-Mutant Tumors

Project description:KRAS is the most frequently mutated oncogene in human cancer, and KRAS inhibition has been a longtime goal. Recently, inhibitors (G12C-Is) that bind KRAS-G12C-GDP and react with Cys-12 were developed. Using new affinity reagents to monitor KRAS-G12C activation and inhibitor engagement, we found that SHP2 inhibitors (SHP2-Is) increased KRAS-GDP occupancy, enhancing G12C-I efficacy. SHP2-Is abrogated feedback signaling by multiple RTKs and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRAS-G12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) models. The combination of SHP2-I and G12C-I evoked favorable changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using an inhibitor-resistant SHP2 mutant showed that SHP2 inhibition in PDAC cells is required for tumor regression and remodeling of the immune microenvironment, but SHP2-Is also had direct effects on angiogenesis. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies. G12C-Is show significant, but limited, efficacy as single agents, in part because of “adaptive resistance”. We find that combining G12C-Is with SHP2-Is abrogates adaptive resistance and results in favorable changes in the immune microenvironment that potentiate PD-1 blockade in KRAS-mutant malignancies. SHP2-Is also can have direct, context-dependent, effects on tumor vasculature.

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KRAS G12C inhibition combined with CD47 and immune checkpoint blockage overcomes intrinsic resistance to concomitant KRAS G12C and immune checkpoint inhibitor therapy

Project description:Although KRAS G12C inhibitors have altered the treatment strategy of patients with KRAS G12C mutant lung cancer, their efficacy is insufficient to eliminate tumors. Here, we identified that inhibition of mutant KRAS promotes escape from macrophage phagocytosis by upregulating the expression of ‘don’t eat me’ signal proteins, including CD47. CD47 was induced by the binding of FOXA1 to the super-enhancer of CD47. The addition of an anti-CD47 antibody restored macrophage phagocytosis and phenotype of macrophages.

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RNA-Seq of KRAS-regulated genes in a murine cell line and lung tumours

Project description:RNA-Seq of KRAS-regulated genes in a murine cell line and lung tumours

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Covalent inhibitor design confers activity against both GDP- and GTP-bound forms of KRAS G12C

Project description:The discovery of KRAS G12C inactive state inhibitors represents a significant advancement in the field of precision oncology. While inactive state inhibition shows promise in patients, SWII-binding inhibitors targeting both inactive and active states remain an underdeveloped therapeutic modality. Here, we describe the discovery of KRAS G12C dual inhibitors that bind the SWII allosteric site using a chemically differentiated warhead to covalently modify both KRAS G12C inactive and active states. Co-crystal structures reveal that these inhibitors perturb a key water-mediated hydrogen bonding network and trigger allosteric remodeling of the GTP-bound protein surface and Switch I to prevent binding to downstream effectors. Consistent with simultaneous targeting of the active and inactive state, dual inhibitors provide rapid covalent target engagement and suppression of MAPK signaling. However, KRAS G12C dual and inactive state inhibitors demonstrate similar efficacy in cellular and in vivo models despite faster target inhibition afforded by targeting the active state. Furthermore, KRAS G12C dual and inactive state inhibitors show similar cellular efficacy in the presence of growth factors that drive KRAS, wt NRAS and wt HRAS to the active state. These data provide the first detailed account of targeting the active and inactive state of KRAS and highlight the absence of a mechanistic advantage in the context of prolonged KRAS G12C inhibition and efficacy.

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Project description:KRAS G12C inhibitors (G12Ci) alone and in various combinations are being tested in multiple tumors with over-activation of the RAS/ERK pathway. KRAS plays a critical role in normal cell signaling; hence, G12Cis could influence the signaling pathways. We found that several novel pathways including Hippo pathways are upregulated upon MRTX849 treatment. Our results argue for testing KRAS G12C and TEAD inhibitor combinations in NSCLC patients.

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Genome-Wide CRISPR Screen Identifies Multiple Synthetic Lethal Targets That Enhance KRAS (G12C) Inhibitor Efficacy [RNA-seq-mm10]

Project description:KRAS G12C inhibitors (G12Ci) alone and in various combinations are being tested in multiple tumors with over-activation of the RAS/ERK pathway. KRAS plays a critical role in normal cell signaling; hence, G12Cis could influence the signaling pathways. We found that several novel pathways including Hippo pathways are upregulated upon MRTX849 treatment. Our results argue for testing KRAS G12C and TEAD inhibitor combinations in NSCLC patients.

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